Nasal carriage of Staphylococcus aureus is a well-defined risk factor for subsequent infection in nearly all categories of hospitalized patients that have been studied. S. aureus carriage has been studied extensively in surgical patients (general, orthopedic, and thoracic surgery), in patients on hemodialysis, in patients on continuous ambulatory peritoneal dialysis (CAPD), HIV-infected patients, and in patients in intensive care units.
The morbidity and mortality and economic impact of surgical-site infections (SSIs) are enormous. SSIs, the most common nosocomial infections among surgical patients, are thought to complicate approximately 500,000 of the estimated 27 million operations performed annually in the United States. S. aureus is the most frequently identified pathogen in SSIs. The estimated annual hospital charges associated with these infections is more than $1.6 billion. SSIs prolong hospital stays by more than 5 days per episode. More importantly, SSI patients are more than twice as likely to die in the postoperative period.
The pathogenicity of S. aureus is normally associated with the ability of a particular strain to produce coagulase enzymes but these organisms contain antigens and produce toxins with superantigenic properties and have been implicated in at least two disease states. S. aureus enterotoxins activate T-cells by binding to the variable beta-chain of the T-cell receptor major histocompatibility class II complex (MHC) outside of the antigen specific groove. Clinical studies demonstrate that bacterial superantigens induce Ig-E synthesis which may have a major impact on upper and lower airway disease such as nasal polyposis and asthma.
Elimination of S. aureus nasal carriage seems to be the most straightforward strategy to prevent the real and potential negative affects of S. aureus in the nasal cavity as well as other areas of the upper respiratory tract which for purposes of the present invention is defined to include the nose, paranasal sinuses, pharynx, trachea, bronchi and the mouth. The introduction of mupirocin ointment in the late 1980s was intended to meet this need. Mupirocin nasal ointment is an effective treatment for eliminating S. aureus. The treatment of carriers with mupirocin in the nasal cavity results in a significant reduction of the nosocomial S. aureus infection rate for hemodialysis and CAPD patients. A review mupirocin studies concluded that treatment of S. aureus carriers with mupirocin in the nasal cavity significantly reduces (50%) of the rate of nosocomial S. aureus infection. Many randomized and non-randomized mupirocin trials indicate that mupirocin nasal treatment of patients prior to surgery reduces Staphylococcus aureus postoperative infection.
Mupirocin resistant strains were described soon after its introduction. Moreover, the increased use of mupirocin, especially for chronic infections, has led to an increased incidence of resistance. In a recent survey from Spain, levels of mupirocin resistance in clinical isolates was reported to have increased for 7.7% in 1998 to 17% in 2000, and some hospitals have reported incidences as high as 63%. The continuing spread of methicillin resistant S. aureus (MRSA) and the increase in mupirocin-resistant strains prevents the prophylactic use of this product and highlights the need for alternative agents. Before mupirocin can be administered to a patient suspected of being a S. aureus carrier they must be tested for the presence of S. aureus in their nasal nares. This requires a medical professional to swab the nasal cavity for subsequent evaluation for the presence of S. aureus by a microbiology laboratory; a process that takes at least 24 hours and often 48 hour.
Most investigators studying mupirocin for elimination of S. aureus carriage in hospitalized patients have commented that prophylactic use or generalized pre-surgical application will lead to increased rates of mupirocin resistant S. aureus. In some cases investigators have looked for alternative treatments to eradicate S. aureus from nasal nares. One well-known antimicrobial agent, polyvinylpyrolodone-iodine (PVP-I), has been investigated by several groups for eradicating S. aureus and MRSA in the nasal cavity.
In these studies PVP-I was diluted to reduce potential toxicity and the results were promising. These investigators point out that PVP-iodine provides useful properties for local anti-infective treatment in general and for surface decontamination in particular. The microbial action spectrum is broad even after short exposure times and no known microbial resistance to iodine occurs. In contrast to antibiotics PVP-I not only destroys bacteria, but also effectively inhibits the release of pathogenic factors, such as exotoxins, endotoxins and tissue-destroying enzymes.
The label claim on iodine-based germicides is based on “total iodine” which is measured by thiosulfate titration. Unfortunately, three species of iodine are titrated by thiosulfate: triiodide, HOI (hypoiodious acid) and I2. The overwhelming majority of the iodine titrated in these germicides exists as triiodide. The high concentrations of iodide, buffering agents (pH<4) and povidone in these germicides are included to improve the stability of the I2 molecule.
The formulators of these compositions did not give consideration to use in the nasal cavity. The prior art applications using iodine in the nasal cavity make no attempt to optimize the efficacy to toxicity properties of these agents as they are intended for use on the skin. When these agents are applied to the skin the only species of iodine that are of concern with respect to systemic toxicity is the I2 species since it is the only species of iodine that can penetrate the skin. When PVP-I is applied to the skin of mammals less than 0.01% of the iodine contained in these compositions is absorbed systemically. Consequently, the amount of iodine that is absorbed systemically is so low that it is not possible to detect the increase in systemic iodine (if any) above the background level. Consequently, the ratio of I2 to other iodine species in complex iodine formulations applied to the epidermis is not a meaningful safety consideration. However, when iodine-based compositions are applied to mucous membranes the risk to the thyroid is distinct. For instance, when PVP-I is administered to the nasal cavity 100% of the iodine administered is absorbed systemically.
Kramer in Dermatology Vol. 204 (Suppl.) 1; 86-91, 2002 examined the irritation potential of iodophors in the nasal cavity and cartilage tissue. The hen's egg-chorioallantoic membrane (HET-CAM) test and explant test was used to evaluate the tolerability of and PVP-I. As shown in the Table below 10% PVP-I inhibits growth.
TABLEGrowth rates in explant test with prepared peritoneal tissue.ExposureGrowth rate %AgentConcentrationmin(control = 100%)PVP-I10% 16310%3040Masano in Postgrad Med J 1993, 69 Suppl 3, S122-5 treated patients and healthcare workers with PVP-I cream. Daily application of 10% PVP-I for 2 months did not induce goiter but the TSH levels in four of seven family members was elevated. These results indicate that iodine, like almost all other chemical and biological ingredients in nasal formulations, is absorbed in the nasal cavity. Kramer and Gluck in Krankenhaus-und Praxishygiene (Hospital and Practice Hygiene); Kramer, A., Heeg, P. et al., Eds.; München, Fischer BEI Elsevier: 2001; pp 252-268 recognized safety concerns related to the use of agents with high levels of iodine and diluted PVP-I to a concentration of 1.25% before application in the nasal cavity. A total of 88 volunteers (77 males and 11 females) were treated twice a day for three days and the principal side effects reported were dryness, itchiness and sneezing. No thyroid dysfunction was observed. The prior art does not describe an approach that provides a composition with a high therapeutic index (ratio of efficacy to side effects).
U.S. Pat. No. 6,171,611 describes a nasal moisturizing saline (0.65%) solution made of water, iodine or an iodine salt that is buffered at physiological pH, namely pH 7.4 but does not identify the basic formulation parameters that would enable one to devise a biocidal composition of matter. The iodine described in U.S. Pat. No. 6,171,611 is either “iodine” or an “iodine salt” selected from the group consisting of ammonium iodate, ammonium iodide, calcium iodate, calcium iodide, iodine monochloride, iodine trichloride, magnesium iodate, magnesium iodide, potassium iodate, potassium iodide, sodium iodate, sodium iodide, zinc iodate and zinc iodide. It is well known to one skilled in the art that these iodide salts are not, biocidal; in fact, at a pH of 7.4 the iodide salts in this group are not biocidal either individually or when combined. Moreover, a pH of 7.4 is not compatible with the I2 species since I2 is not stable at a pH of 7.4 and at a pH of 7.4 the I2 species hydrolyzes very rapidly to form other species of iodine including iodide, HOI, iodate and triiodide. U.S. Pat. No. 5,962,029 describes the hydrolysis of I2 at a pH of 7 and above. At a pH of 7.0 about 21% of the I2 is hydrolyzed in one hour; at a pH of 8.0 the loss increases to 78% in one hour. This is not a new observation since the rate of hydrolysis of I2 was first published over 50 years ago by Wyss in Arch Biochem 1945, 6, 261-268.
König et al. in Dermatology 1997, 195 Suppl 2, 42-48 studied the effect of PVP-I on polymorphonuclear leukocytes (PMN) cells. PMN cells play a role in the immune response by engulfing a foreign pathogen and processing it prior to presenting the processed antigen to the immune system. PMN cells engulf a pathogen using a process known as phygocytosis. Following phagocytosis, the pathogen is moved into a phagolysozome where degredative enzymes actively lyse the pathogen. When pathogens are lysed they release proteins like TNF-α which can stimulate an immune response. Immune responses like these are well known in several medical conditions including atopic dermatitis, eczema, psoriasis, impetigo and sinusitis. König et al. combined a S. aureus strain of unknown enterotoxin status with various concentrations of PVP-I, added PMN cells and then incubated the mixture for 6 hours. The data indicate that PMN cells released increasing amounts of TNF-α as PVP-I is diluted demonstrating PVP-I inactivation of the cytokine TNF-α after its release from PMN cells. The PVP-I reaction observed by König was a PMN-specific response (recognition-phagocytosis-processing).
Hill and Casewell J Hosp Infect 2000, 45, 198-205 demonstrated that the nasal secretions from 11 different samples reduced the biocidal activity of PVP-I. They calculated that 1.0 milliliter of nasal secretions inactivated the equivalent of approximately 22.5 mg of PVP-I. This is not a surprising result since it is known that the nose has a well defined mucociliary apparatus. Airway mucus consists of two layers, a low vicoelasticity periciliary layer that envelops the cilia, and a more viscous layer that rides on top of the periciliary layer. The primary glycoproteins that comprise nasal mucous are mucins. Mucins contain a very high concentration of cysteine which can react with I2 and thereby neutralize its activity. Consequently, it is necessary to insure a minimum I2 concentration that can overcome whatever residual mucin resides in the nasal cavity.
Given the presence of a bioburden in the nasal cavity, one of the key formulation parameters is the minimum concentration of biocidal iodine (i.e., I2) required for efficacy. In theory, the concentration of I2 is a function of the amount of material that is contacted to the interior of the nasal cavity. In practice, it is only feasible to use about 0.25 grams of material per nostril if the formulation is provided in the form of a gel, cream or ointment and no more than two times that amount (i.e., 0.5 grams per nostril) if the formulation is delivered as a liquid in the form of nose drops or a spray. U.S. Pat. No. 6,171,611 claims a lower concentration range of 0.001% iodine by weight which is equivalent to 10 ppm I2 (assuming that all of the iodine species were present in the biocidal form). It has been found in accordance with the present invention that a concentration of 10 ppm I2 is not adequate to eliminate S. aureus when the formulation is provided as a gel. Even when the composition is sprayed into the nasal cavity, thereby allowing a larger number of I2 molecules to contact the mucous membranes of the nasal cavity, a 10 ppm composition is not adequate to overcome the bioburden associated with endogenous mucin.